Ophthalmic Drug Delivery

ABSTRACT

The present invention includes and provides a method of delivering a medicament to an eye of a subject in need thereof a solution, the method comprising: (a) providing droplets containing the medicament with a specified average size and average initial ejecting velocity; and (b) delivering the medicament to the eye, where the droplets deliver a percentage of the ejected mass of the droplets to the eye.

RELATED APPLICATIONS

The present application claims the benefit of the filing date of U.S.Provisional Application No. 61/400,864, filed Jul. 15, 2010, U.S.Provisional Application No. 61/401,850, filed Aug. 20, 2010, U.S.Provisional Application No. 61/401,920 filed Aug. 20, 2010, U.S.Provisional Application No. 61/401,918 filed Aug. 20, 2010, U.S.Provisional Application No. 61/401,848 filed Aug. 20, 2010, U.S.Provisional Application No. 61/401,849 filed Aug. 20, 2010, U.S.Provisional Application No. 61/462,576 filed Feb. 4, 2011, U.S.Provisional Application No. 61/462,791 filed Feb. 5, 2011, U.S.Provisional Application No. 61/463,280 filed Feb. 15, 2011, U.S.Provisional Application No. 61/516,462, filed Apr. 4, 2011, U.S.Provisional Application No. 61/516,496 filed Apr. 4, 2011, U.S.Provisional Application No. 61/516,495 filed Apr. 4, 2011, and U.S.Provisional Application No. 61/516,694, filed Apr. 6, 2011, the entirecontents of each of which is specifically hereby incorporated byreference for all purposes. The present application is also related toU.S. Provisional Application No. 61/396,531 filed May 28, 2010, theentire contents of which is specifically hereby incorporated byreference for all purposes.

FIELD OF THE INVENTION

The present invention relates to devices for the generation of ejecteddroplets, methods of administration and uses thereof, and medicamentcompositions formulated therefor.

BACKGROUND OF THE INVENTION

A typical medical droplet as dispensed by an eye dropper bottle canvary, depending on the viscosity and surface tension of the fluid. Inorder to control the amount of active ingredient that is administered ina single droplet, the concentration of the active ingredient is adjustedby volume. Once the concentration is defined, a correct dosage mayrequire one drop or more. However, since the human eye can typicallyretain only 7 μl of fluid at a time, even a single medical droplet canresult in overflow and loss of part of the medication from the eye.Multiple drop dosage often compounds the problem of medication retentionin the eye. Subjects will typically administer all droplets required fora dosage in one sitting, which exacerbates the problem and can result in50 to 90% of the medication overflowing and leaking out of the eye.

Another further problem is that a single droplet of the definedconcentration marks the lower limit of a dose and, as such, the amountof active ingredient that can be administered at the definedconcentration. For example, pediatric application where lower doses areoften advisable are an illustration of where the size/dose of a dropletcan be problematic.

Given the above and other limitations of current ophthalmic delivery, aneed exists for an efficient delivery system for solutions to the eye,including solutions containing medicaments.

SUMMARY OF THE INVENTION

To address such needs and others, provided herein are stable medicamentcompositions and uses thereof.

One embodiment provides a method of delivering a medicament to an eye ofa subject in need thereof a solution, the method comprising: (a)providing droplets containing the medicament, where said droplets havean average drop size of between about 15 microns and about 100 micronsin diameters and an average ejecting velocity of between about 0.5 m/sto about 20 m/s; and (b) delivering the medicament to the eye, wherebetween about 80% to about 100% of the ejected mass of the droplets aredeposited on the eye.

Another embodiment provides a method of delivering a medicament solutionto a subject in need thereof by controlling droplet size and dropletdeposit parameters of the medicament solution, the method comprising:(a) determining desired dosage of the medicament solution for thesubject in need thereof; and (b) providing the desired dosage in asingle application by determining the droplet size and depositparameters.

Yet another embodiment provides a method for providing a solution to theeye, the method comprising: (a) providing droplets containing themedicament, having an average droplet size of between about 15 micronsand about 100 microns in diameter and an average initial ejectingvelocity of between about 0.5 m/s to about 20 m/s; and (b) deliveringthe medicament to the eye, where between about 80% to about 100% of theejected mass of the droplets are deposited on the eye.

These and other aspects of the invention will become apparent to one ofskill in the art.

DETAILED DESCRIPTION OF THE INVENTION A. Methods of Generating EjectedDroplets

The present invention provides an effective approach to undertake dosingstrategies. Dosing strategies also will incorporate various approachesto initiating treatment, stopping treatment, switching treatment andresponding to different subject states.

Examples of dosing modes or strategies include night timeadministration, administration before waking, increased administrationone week a month, three times a day, continuous dosing, bolus dosing,taper dosing, need-based dosing, and feedback dosing by the physician,provider, subject or family. The clinical scenarios where these can beemployed include chronic disease, disease exacerbation, need forsuppression treatment, need for recurrence treatment, or state oftreatment like medicament tolerance.

B. Methods of Delivery and Treatment

Provided is a method of delivering a medicament to an eye of a subjectin need thereof a solution, the method comprising: (a) providingdroplets containing the medicament with a specified average size andaverage initial ejecting velocity; and (b) delivering the medicament tothe eye, where the droplets deliver a percentage of the ejected mass ofthe droplets to the eye.

Devices capable of providing and delivering a fluid such as ophthalmicfluid to the eye are provided. In certain aspects, ejection devicesinclude an ejection assembly which generates or provides a controllablestream of droplets of fluid. Fluids include, without limitation,suspensions and emulsions which have viscosity in a range capable ofdroplet formation using an ejector mechanism. As explained in furtherdetail herein, in accordance with certain aspects of the presentdisclosure, the actuator mechanism may form a directed stream ofdroplets, which may be directed toward a target. The droplets will beformed in distribution of sizes, each distribution having an averagedroplet size. The average droplet size may be in the range of about 15microns to about 100 microns, about 20 microns to about 100 microns,greater than 20 microns to about 100 microns, about 20 microns to about80 microns, about 25 microns to about 75 microns, about 30 microns toabout 60 microns, about 35 microns to about 55 microns, etc. However,the average droplet size may be as large as 2500 microns, depending onthe intended application. Further, the droplets may have an averageinitial ejecting velocity of about 0.5 m/s to about 20 m/s, e.g., about1 m/s to about 10 m/s, about 1 m/s to about 5 m/s, about 1 m/s to about4 m/s, about 2 m/s, etc. As used herein, the ejecting size and theejecting initial velocity are the size and velocity of the droplets whenthe droplets leave the ejector plate. The stream of droplets directed ata target will result in deposition of a percentage of the mass of thedroplets including their composition onto the desired location.

The disclosed technology will eject droplets without substantialevaporation, entrainment of air, or deflection off the eye surface,which facilitates consistent dosing. Average ejecting droplet size andaverage initial ejecting velocity are dependent on factors includingfluid viscosity, surface tension, ejector plate properties, geometry,and dimensions, as well as operating parameters of the piezoelectricactuator including its drive frequency. In some implementations, about60% to about 100%, about 65% to about 100%, about 75% to about 100%,about 80% to about 100%, about 85% to about 100%, about 90% to about100%, about 95% to about 100%, etc., of the ejected mass of droplets aredeposited on the surface of the eye, such deposition being repeatableindependent of operating and use conditions. The direction of flow ofthe stream of droplets may be horizontal, or any direction a userchooses to aim the actuation mechanism during use.

Droplet performance is generally related to particle diameter. Withoutintending to be limited, ejected droplets are slowed to a stop by airdrag (i.e., stopping distance of the ejected droplets). Ejected dropletsalso fall vertically due to gravity. After a short acceleration time,the droplets reach terminal velocity where the drag force equals theforce of gravity. The ejected droplets may carry air along with them,which creates an entrained airstream, which aids to then carry theejected droplets beyond the calculated stopping distance. However,increased levels of entrained air may cause the ejected droplets to flowacross an impact surface (e.g., an eye surface) because the entrainedairflow must turn 90 degrees at such a surface. Small, ejected droplets(e.g., droplets having an average diameter less than about 17 microns,less than about 15 microns, etc.) are carried along the surface of theeye by the airstream and may not impact the surface. Contrasted to this,larger ejected droplets create less entrained air than an equivalentmass of smaller droplets, and have enough momentum to impact thesurface. The ejected droplet stopping distance is a measure of thiseffect.

Also provided is a method of delivering a medicament solution to asubject in need thereof by controlling droplet size and depositparameters of the medicament solution, the method comprising: (a)determining desired dosage of the medicament solution for the subject inneed thereof; and (b) providing the desired dosage in a singleapplication or multiple applications by determining the droplet size anddeposit parameters.

Many factors, including those described herein, can influence thedesired dosage. Once the desired dosage is determined, and also ifdesired frequency, such doses can be delivered. Frequency of dosing canvary by number of times, periodicity or both.

Also provided is a method for providing a solution to the eye, themethod comprising: (a) providing droplets containing the solution, wherethe droplets have an average drop size in diameter and an averageinitial ejecting velocity; and (b) delivering the solution to the eye,where between about 80% to about 100% of the ejected mass of thedroplets are deposited on the eye.

Further provided is a method of treating eye condition disorders,including glaucoma, infection or other eye indications, and relateddiscomforts or other need in a subject in need thereof, the methodcomprising: (a) providing droplets containing said medicament with aspecified average size and average initial ejecting velocity; and (b)delivering the medicament to the eye, where the droplets deliver apercentage of the ejected mass of the droplets to the eye.

Further provided is a method of providing a reduced dosage form of amedicament to an eye comprising: (a) providing droplets containing themedicament, where the droplets have an average drop size and an averageinitial ejecting velocity; and (b) delivering the medicament to the eye,where the droplets deliver a specified deposited mass of the droplets.In this or other aspects, the droplets can provide a total volume ofless than 30 μl, 20 μl, 15 μl, 10 μl, 5 μl or 2 μl to eye.

C. Ejector Device

Exemplary ejector devices capable of generating droplets of the typedescribed herein are provided in US Application Attorney Docket No.24591.003-US03, filed concurrently herewith, entitled “Drop-GeneratingDevice”, herein incorporated by reference in its entirety. In one aspectof one such device an ejector plate is coupled to an actuator. Themanner and location of attachment of the actuator to the plate affectsthe operation of the ejection assembly and the creation of the dropletstream with the option of the actuator being a piezoelectric actuator.

D. Medicament and Other Compositions

Any medicament showing a desired ophthalmic activity may beadministered. In an aspect, the medicament is available by prescription.In another aspect, the medicament is available over-the-counter. In anaspect, the medicament is or comprises a biologic agent. In an aspect,the biologic agent is selected from the group consisting of afull-length antibody, an active fragment of a full-length antibody, apeptide, a pegylated peptide, and an enzymatic ingredient. In anotheraspect, the biologic ingredient is selected from the group consisting ofbevacizumab, ranibizumab, FV fragments, bi-specific antibodies, fusionmolecules, pegaptanib, plasmin and microplasmin. In a further aspect,the biologic agent is selected from the group consisting of ranibizumabantibody FAB (including Lucentis™), VEGF Trap fusion molecule (includingVEGF Trap-Eye™), microplasmin enzyme (including Ocriplasmin™), macugenpegylated polypeptide (including Pegaptanib™), and bevacizumab(including Avastin™).

In another aspect, a medicament to be administered is or comprises asmall molecule. In an aspect, the medicament to be administeredcomprises a medicament selected from the group consisting ofcyclosporine, neomycin, biomonidine, and aminoglycoside antibiotics,including, for example, tobramycin and gentamycin.

In various aspects, a solution may have different salinity. Salinity maybe measured using a hydrometer. In various aspects, salinity may rangefrom 0%, or a pure aqueous solution, to 2.5%. In other aspects, salinitymay range from about 0.1% to about 1%, from about 0.5% to about 1%, fromabout 0.7% to about 1%, from about 0.8% to about 1%. In further aspects,salinity of a medicament may be about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%,0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, or about 1.5%. Inother aspects, salinity may be less than about 1.5%, less than about 1%,less than about 0.5% or less than about 0.2%. In an aspect, the solutionis isotonic with the site of delivery. For example, in various aspects,the medicament may be isotonic with human tears, blood, or eye tissue.

In an aspect, the medicament to be delivered comprises a medicamentselected from the group consisting of carboxymethylcellulose sodium,tetrahydrozoline HCl, pheniramine maleate, ketotifen fumarate,oxymetazoline HCl, naphazoline HCl, pheniramine maleate, moxifloxacinhydrochloride, bromfenac, proparacaine hydrochloride, difluprednate,gatifloxacin, travoprost, bepotastine besilate, gatifloxacin,loteprednol etabonate, timolol ophthalmic, olopatadine hydrochloride,phenylephrine hydrochloride, levofloxacin, ketorolac tromethamine,letanoprost, bimatoprost and BAK free latanoprost. In another aspect,the medicament is selected from the group consisting of Refresh Tears™,Visine Advanced Relief™, Naphcon A™, Sensitive Eyes™, Renu™, Opti-Free™rewetting drops, Visine A.C.™, Hypo Tears™, Alaway™, Visine L.R.™,Visine™ original, Rohto Cool™, Soothe XP™, Zaditor™, Bausch & LombAdvanced Eye Relief Redness™, Visine A™, Opcon-A™, Walgreens artificialtears, Visine™ dry eye relief, Advanced Eye Relief Dry Eye™, Opti-freeReplenish™, Clear Eyes™ redness relief, Vigamox™, Bromday™, Durezol™,Zymaxid™, Travatan Z™, Tropicamide™, Bepreve™, Zymar™, Lotemax™,Istalol™, Pataday™, AK-Dilate™, Toradol™, Xalatan™, and Lumigan™.

In another aspect, the medicament to be delivered comprises a medicamentselected from the group consisting of fluorosilicone acrylate, sodiumcarboxymethylcellulose, hydroxypropyl methylcellulose, tetrahydrozolineHCl, carboxymethylcellulose sodium, propylene glycol, hypromellose, zincsulfate, dorzolamide HCl timolol maleate, azithromycin, brimonidinetartrate, nepafenac, brinzolamide, besifloxacin, dorzolamide HCl,prenisone acetate, loteprednol etabonate, tobramycin/dexamethasone, andcyclosporine. In a further aspect, the medicament is selected from thegroup consisting of Tears Naturale II™, Optimum NWN™, Thera Tears™,Systane Ultra™, GenTear™, Systane Lubricant Eye Drops™, Blink™ tears,Visine Max Redness Relief™, Refresh Optive™, Muro 128™, SystaneBalance™, Rohto Hydra™, Rohto Ice™, Walgreens sterile artificial tears,Rohto Arctic™, Clear Eyes™ natural tears lubricant, Similasan™ pink eyerelief, Similasan™ allergy eye relief, Cosopt™, AzaSite™ Alphagan P™,Nevanac™, Azopt™, Besivance™ Trusopt™, Alrex™, and Restasis™.

In an aspect, an ophthalmic medicament to be delivered is used to treatglaucoma. In an aspect, a glaucoma medicament is selected from the groupconsisting of travoprost, timolol ophthalmic, latanoprost, bimatoprost,dorzolamide HCl timolol maleate, brimonidine tartrate, brinzolamide,dorzolamide HCl, and BAK free latanoprost. In a further aspect, amedicament is selected from the group consisting of travoprost, timololophthalmic, latanoprost, bimatoprost, and BAK free latanoprost. Inanother aspect, a medicament is selected from the group consisting ofdorzolamide HCl timolol maleate, brimonidine tartrate, brinzolamide, anddorzolamide HCl. In an aspect, a glaucoma medicament is selected fromthe group consisting of Travatan™, Istalol™, Xalatan™, Lumigan™,Cosopt™, Alphagan P™, Azopt™, and Trusopt™. In another aspect, amedicament is selected from the group consisting of Travatan™, Istolol™,Xalatan™, and Lumigan™. In a further aspect, a medicament is selectedfrom the group consisting of Cosopt™, Alphagan P™, Azopt™, andDorzolamide HCl™.

In an aspect, the concentration of an active ingredient in a medicamentis measured as a percentage of the active ingredient in solution. In anaspect, the concentration of active ingredient ranges from about 0.0001%to about 5%. In another aspect, the concentration of active ingredientin a medicament ranges from about 0.0005% to about 1%. In other aspects,the concentration of active ingredient ranges from about 0.0005% toabout 0.0001%, from about 0.0001% to about 0.001%, or from about 0.0005%to about 0.001%. In other aspects, the concentration of activeingredient ranges from about 0.005% to about 0.001% or from about 0.001%to about 0.01%. In another aspect, the concentration of activeingredient ranges from about 0.001% to about 0.5%. In various otheraspects, the concentration of active ingredient is selected from thegroup consisting of about 0.0001%, about 0.0005%, about 0.001%, about0.0025%, about 0.005%, about 0.01%, about 0.025%, about 0.05%, about0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.75%, about1%, about 1.5%, about 2%, about 2.5%, about 3%, about 4%, and about 5%measured as a percentage of the solution. However, given the lowerdosing amounts afforded by the methods of the present disclosure, higherconcentrations may be used depending on the intended use. For examples,about 10%, about 20%, about 25%, of the active ingredient in themedicament, measured as a percentage of the solution, may be utilized.

In an aspect, the medicament comprises a medicament selected from thegroup consisting of between about 0.02% and about 0.03%carboxymethylcellulose sodium, between about 0.4% and about 0.6%carboxymethylcellulose sodium, between about 0.04% and about 0.06%tetrahydrozoline HCl, between about 0.04% and about 0.06%tetrahydrozoline HCl, between about 0.24% and about 0.36% pheniraminemaleate, between about 0.02% and about 0.03% ketotifen fumarate, betweenabout 0.028% and about 0.042% ketotifen fumarate, between about 0.02%and about 0.03% oxymetazoline HCl, between about 0.0096% and about0.0144% naphazoline HCl, between about 0.024% and about 0.036%naphazoline HCl, between about 0.24% and 0.36% pheniramine maleate,between about 0.4% and about 0.6% moxifloxacin hydrochloride, betweenabout 0.072% and about 0.108% bromfenac, between about 0.4% and about0.6% proparacaine hydrochloride, between about 0.04% and about 0.06%difluprednate, between about 0.4% and about 0.6% gatifloxacin, betweenabout 0.0032% and about 0.0048% travoprost, between about 1.2% and about1.8% bepotastine besilate, between about 0.24% and about 0.36%gatifloxacin, between about 0.4% and about 0.6% loteprednol etabonate,between about 0.4% and about 0.6% timolol ophthalmic, between about0.16% and about 0.24% olopatadine hydrochloride, between about 2% andabout 3% phenylephrine hydrochloride, between about 0.4% and about 0.6%levofloxacin, between about 0.32% and about 0.48% ketorolactromethamine, between about 0.004% and about 0.006% letanoprost, andbetween about 0.024% and about 0.036% bimatoprost.

In an aspect, the medicament comprises a medicament selected from thegroup consisting of 0.025% carboxymethylcellulose sodium, 0.5%carboxymethylcellulose sodium, 0.05% tetrahydrozoline HCl, 0.5%,tetrahydrozoline HCl, 0.3% pheniramine maleate, 0.025% ketotifenfumarate, 0.035% ketotifen fumarate, 0.025% oxymetazoline HCl, 0.012%naphazoline HCl, 0.03% naphazoline HCl, 0.3% pheniramine maleate, 0.5%moxifloxacin hydrochloride, 0.09% bromfenac, 0.5% proparacainehydrochloride, 0.05% difluprednate, 0.5% gatifloxacin, 0.004%travoprost, 1.5% bepotastine besilate, 0.3% gatifloxacin, 0.5%loteprednol etabonate, 0.5% timolol ophthalmic, 0.2% olopatadinehydrochloride, 2.5% phenylephrine hydrochloride, 0.5% levofloxacin, 0.4%ketorolac tromethamine, 0.005% letanoprost, and 0.03% bimatoprost.

In another aspect, the medicament to be delivered comprises a medicamentselected from the group consisting of between about 0.02% and about 0.3%sodium carboxymethylcellulose, between about 0.04% and about 0.06%tetrahydrozoline HCl, between about 0.4% and about 0.6%carboxymethylcellulose sodium, between about 0.48% and about 0.72%propylene glycol, between about 0.24% and about 0.36% hypromellose,between about 0.2% and about 0.3% zinc sulfate, between about 0.8% andabout 1.2% azithromycin, between about 0.08% and about 0.12% brimonidinetartrate, between about 0.08% and about 0.12% nepafenac, between about0.8% and about 1.2% brinzolamide, between about 0.48% and about 0.72%besifloxacin, between about 1.6% and about 2.4% dorzolamide HCl, betweenabout 0.8% and about 1.2% prenisone acetate, between about 0.16% andabout 0.24% loteprednol etabonate, between about 0.32% and about 0.48%tobramycin/dexamethasone, and between about 0.04% and about 0.06%cyclosporine.

In another aspect, the medicament to be delivered comprises a medicamentselected from the group consisting of 0.025% sodiumcarboxymethylcellulose, 0.05% tetrahydrozoline HCl, 0.5%carboxymethylcellulose sodium, 0.6% propylene glycol, 0.3% hypromellose,0.25% zinc sulfate, 1% azithromycin, 0.1% brimonidine tartrate, 0.1%nepafenac, 1% brinzolamide, 0.6% besifloxacin, 2% dorzolamide HCl, 1%prenisone acetate, 0.2% loteprednol etabonate, 0.4%tobramycin/dexamethasone, and 0.05% cyclosporine.

In an aspect, the medicament to be administered is not water-soluble. Inanother aspect, the medicament to be administered is poorlywater-soluble. In a preferred aspect, the medicament is water-soluble,highly water-soluble, or very highly water-soluble. In an aspect, poorlywater soluble is less than 10 ug/mL. In other aspects, water soluble is10 to 60 ug/mL, highly water soluble is greater than 60 to 120 ug/mL,and very highly water soluble is greater than 120 ug/mL.

In another aspect, the medicament to be administered is formulated in anemulsion or a suspension. In an aspect, the medicament to be deliveredcomprises difluprednate or loteprednol etabonate. In an aspect, themedicament is Durezol™ or Lotemax™.

As generally understood by those skilled in the art, the listing of anactive agent includes medicamently acceptable salts, esters, and acidsthereof.

In an aspect, a medicament to be delivered comprises a preservative orother additive acceptable for use in the eye. In an aspect, a medicamentcomprises 20% or less of a preservative or other additive, or 15% orless, 12% or less, 10% or less, 8% or less, 6% or less, 5% or less, 4%or less, 3% or less, 2% or less, 1% or less, 0.5% or less, 0.4% or less,0.3% or less, 0.2% or less, 0.1% or less of a preservative or otheradditive.

In another aspect, the medicament to be delivered comprises a polymericingredient. In an aspect, the medicament comprises an additive selectedfrom the group consisting of glycerin, castor oil, carbomer,polyethylene glycol, and polysorbate 80. In an aspect, the concentrationof polymer is measured as a percentage of the total solution by weight.In various aspects, the medicament comprises 10% or less of a polymer,5% or less of a polymer, 4% or less of a polymer, 3% or less of apolymer, 2% or less of a polymer, 1.5% or less of a polymer, 1% or lessof a polymer, 0.5% or less of a polymer, 0.4% or less of a polymer, 0.3%or less of a polymer, 0.2% or less of a polymer, 0.1% or less of apolymer, 0.05% or less of a polymer, or no detectable polymer. Invarious aspects, the medicament comprises 10% or less glycerin, 5% orless glycerin, 4% or less glycerin, 3% or less glycerin, 2% or lessglycerin, 1.5% or less glycerin, 1% or less glycerin, 0.5% or lessglycerin, 0.4% or less glycerin, 0.3% or less glycerin, 0.2% or lessglycerin, 0.1% or less glycerin, 0.05% or less glycerin, or no glycerin.

In various aspects, the medicament may have different tonicity. Tonicitymay be measured using a hydrometer. In various aspects, tonicity mayrange from 0%, or a pure aqueous solution, to 2.5%. In other aspects,tonicity may range from 0.1% to 1%, from 0.5% to 1%, from 0.7% to 1%,from 0.8% to 1%. In further aspects, tonicity of a medicament may be0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%,1.3%, 1.4%, or 1.5%. In an aspect, the medicament is isotonic with thesite of delivery. For example, in various aspects, the medicament may beisotonic with human tears, blood, or eye tissue. It is contemplated thata solution with no active ingredient can be administered, e.g., awetting agent.

In an aspect, the subject is less than 150 kilograms, 100 kilograms,less than 50 kilograms, less than 25 kilograms, or less than 10kilograms. In this or other aspects, the subject may be less than 12 or13 years old. In this or other aspects, the subject could be classifiedas human, male or female. In this or other aspects, the subject may bean agricultural animal. In this or other aspects, the subject may benon-human.

The viscosity of the medicament to be administered can vary. Viscosityof a medicament formulation can be measured by using a viscometer. Invarious aspects, viscosity of a medicament at 25° C. ranges from about0.3 to about 300 cP, from about 0.3 to about 200 cP, from about 0.3 toabout 100 cP, from about 0.3 to about 50 cP, from about 0.3 to about 40cP, from about 0.3 to about 30 cP, from about 0.3 to about 20 cP, fromabout 0.3 to about 10 cP, from about 0.3 to about 5 cP, from about 0.3to about 2 cP, from about 0.3 to about 1.5 cP, from about 0.3 to about 1cP, from about 0.3 to about 0.9 cP, from about 0.3 to about 0.8 cP, fromabout 0.3 to about 0.7 cP from about 0.3 to about 0.6 cP, from about 0.3to about 0.5 cP, or from about 0.3 to about 0.4 cP. In various otheraspects, viscosity of a medicament to be administered is about 0.4 toabout 1.4 cP, about 0.5 to about 1.3 cP, about 0.6 to about 1.2 cP,about 0.7 to about 1.1 cP, or about 0.8 to about 1.0 cP at room 25° C.In various other aspects, viscosity of a medicament at 25° C. is about0.3 cP, about 0.4 cP, about 0.5 cP, about 0.6 cP, about 0.7 cP, about0.8 cP, about 0.9 cP, about 1 cP, about 1.1 cP, about 1.2 cP, about 1.3cP, about 1.4 cP, or about 1.5 cP.

In some aspects, the active agents may exhibit increased stabilityand/or solubility at acid or alkaline pH and may be centrallyadministered in such form. In other aspects, a physiologically suitablepH (e.g., in the range of about pH 6.8-8.2, depending on the part of theeye) may be preferred for ophthalmic administration. However, titrationto physiological pH may result in solubility and/or stability issues formany active agents. Therefore, it may be preferred in some cases todevelop aqueous formulations in which the active agent is formulatedwith a solubility-enhancing agent or stabilizing excipients at aphysiologically suitable pH. If titration is desired, any suitablebuffer known in the medicament arts may be used (e.g., phosphate,acetate, glycine, citrate, imidazole, TRIS, MES, MOPS).

Further it may be desirable to maintain physiological isotonicity. Forinstance, in certain aspects, an osmolality ranging from about 100 toabout 1000 mmol/kg, more particularly from about 280 to about 320mmol/kg may be desired. Any suitable manner of adjusting tonicity knownin the pharmaceutical arts may be used, e.g., adjustment with NaCl.

In accordance with certain aspects of the invention, medicamentcompositions are designed to maximize solubility and stability inophthalmic applications and under conditions of use for administrationto the eye.

1. Solubility Enhancing Agents

Again, in accordance with certain aspects of the invention, formulationactive agents in aqueous solutions at physiological pH and tonicity areundertaken. However, to provide adequate solubility to the composition,the use of solubility enhancing agents may optionally be required.

Without intending to be limited by theory, in certain aspects,solubility enhancing agents may utilize their amphiphiliccharacteristics to increase the solubility of active agents in water. Asgenerally understood by those skilled in the art, a wide variety ofsolubility enhancing agents that possess both nonpolar and hydrophilicmoieties may be employed in connection with the present invention.However, amphiphilic agents possessing stronger hydrophobic characterhave the potential to interact with cell membranes and produce toxiceffects. Therefore, again, without intending to be limited by theory,solubility enhancing agents with minimal hydrophobic character may bepreferred in certain aspects within the context of the presentinvention, as such agents will be well-tolerated.

In addition to minimizing the hydrophobic character of the solubilizingagents employed, toxicity during administration may be reduced if thesolubility enhancing agent is readily degraded in a cellularenvironment. The ability of cells to degrade compounds prevents theiraccumulation during chronic administration. To this end, the solubilityenhancing agents may optionally include chemically-labile ester andether linkages that contribute to low toxicity, and thereby preventsignificant cellular accumulations during chronic administration.

In this regard, in accordance with certain aspects of the invention, thesolubility-enhancing agent includes those that can be selected fromcyclodextrins, e.g., β-hydroxypropyl-cyclodextrin, sulfobutyl-ether-βcyclodextrin, etc.

In other aspects, the solubility-enhancing agent may be selected fromsucrose esters. Such agents are formed of two benign components (sucroseand fatty acids) linked by a highly labile ester bond. Although areadily-degradable linkage is beneficial from a toxicity standpoint, thesolubility enhancing agent must be sufficiently robust to maintain itsability to solubilize the active agent during the desired conditions ofuse.

Generally, certain compositions of the invention may be prepared byformulating the desired amount, which may be a therapeutically-effectiveamount, of the desired active agent in a suitable solubility enhancingagent. Solubility enhancing agents include, but are not limited to,e.g., cyclodextrins, octylglucoside, pluronic F-68, Tween 20, sucroseesters, glycerol, ethylene glycol, alcohols, propylene glycol, carboxymethyl cellulose, solutol, mixtures thereof, etc. Othersolubility-enhancing agents include, but are not limited to,polyethylene glycol (PEG), polyvinlypyrrolidone (PVP), arginine,proline, betaine, polyamino acids, peptides, nucleotides, sorbitol,sodium dodecylsulphate (SDS), sugar esters, other surfactants, otherdetergents and pluronics, and mixtures thereof. Alternatively, stablemultiphase systems could be employed to safely solubilize therapeuticsfor intrathecal delivery (e.g., liposomes, micro/nano emulsions,nanoparticles, dendrimers, micro/nano spheres).

Any suitable amount of solubility enhancing agent sufficient tosolubilize the active agent of interest to the desired concentration maybe used. In certain aspects, molar ratios of active agent tosolubility-enhancing agent ranging from about 0.5:1 to about 1:10,particularly, about 1:1 to about 1:5, more particularly 1:1 to about1:2, may be used to achieve adequate solubility of the active agent tothe desired concentrations.

2. Stabilizing Excipients

In addition to solubility, the active agent must be sufficiently stablewithin the composition to withstand hydrolytic and oxidative degradationin order to maintain biological activity during administration. Activeagents generally possesses the therapeutic effects observed duringconventional administration; the stability of the medicament in thecomposition prior to central administration is also of importance. Tothis end, in certain aspects, the compositions of the present inventionmay further include stabilizing excipients and buffers acceptable foruse in the eye.

Considering that oxidation represents a common degradation pathway, incertain aspects, the compositions of the invention may be deoxygenated(e.g., by saturating with nitrogen gas) to minimize the formation ofreactive oxygen species that would degrade the active agent duringstorage. Another method would be to ensure that formulations are storedin a container that does not allow passage of light, thereby minimizingphoto-induced degradation. In addition, in accordance with certainaspects of the invention, stabilizing excipients may optionally be usedto, e.g., prevent or slow degradation by oxidation and/or hydrolysis ofthe active agents. For example, vitamin E, methionine, chelators andmannitol may be used to reduce oxidative degradation. Since the rates ofmany degradation reactions are pH-dependent, such formulations mayinclude any suitable buffering agent known in the art (e.g., phosphate,acetate, glycine, citrate, imidazole, TRIS, MES, MOPS).

Stabilizing excipients useful in the context of the compositionsdescribed herein include any medicamently acceptable components whichfunction to enhance the physical stability, and/or chemical stability ofthe active agent in the compositions of the invention. The medicamentcompositions described herein may include one or more stabilizingexcipients, and each excipient may have one or more stabilizingfunctions.

In one aspect, the stabilizing excipient may function to stabilize theactive agent against chemical degradation, e.g., oxidation, deamidation,deamination, or hydrolysis. In this regard, the stabilizing excipientsmay optionally be selected from antioxidants, such as ascorbic acid(vitamin C), vitamin E, tocopherol conjugates, tocopherol succinate,PEGylated tocopherol succinate, Tris salt of tocopherol succinate,Trolox, mannitol, sucrose, phytic acid, trimercaprol or glutathione.

The term “effective amount” refers to an amount of an active agent usedto treat, ameliorate, prevent, or eliminate the identified ophthalmiccondition (e.g., disease or disorder), or to exhibit a detectabletherapeutic or preventative effect. The effect can be detected by, forexample, chemical markers, antigen levels, or time to a measurableevent, such as morbidity or mortality. The precise effective amount fora subject will depend upon the subject's body weight, size, and health;the nature and extent of the condition; and the therapeutic orcombination of therapeutics selected for administration. Effectiveamounts for a given situation can be determined by routineexperimentation that is within the skill and judgment of the clinician.Any of the agents can be provided in an effective amount.

For any active agent, the effective amount can be estimated initiallyeither in cell culture assays, e.g., in animal models, such as rat ormouse models. An animal model may also be used to determine theappropriate concentration range and route of administration. Suchinformation can then be used to determine useful doses and routes foradministration in humans.

To assist in understanding the present invention, the following Exampleis included. The experiments described herein should not, of course, beconstrued as specifically limiting the invention and such variations ofthe invention, now known or later developed, which would be within thepurview of one skilled in the art are considered to fall within thescope of the invention as described herein and hereinafter claimed.

U.S. Application Attorney Docket Number 24591.003-US03, filedconcurrently herewith, entitled “Drop-Generating Device” and U.S.Application Attorney Docket Number 24591.003-US02, filed concurrentlyherewith, entitled “Method and System for Performing Remote Treatmentand Monitoring” are also each herein incorporated by reference in theirentireties.

Example

Table A describes quantification of average droplet size and the maximumnumber of doses of various medications from individual eyedroppercontainers. Each experiment is repeated in three trials to calculate amore accurate average droplet size. By taking the volume of individualbottles and dividing it by the average droplet size, the maximum numberof doses per eyedropper is calculated.

Column A contains the retail name of medications. In column B, theconcentration of active ingredient of medication is listed as apercentage where publically available. Column C contains the name ofpreservative used in the medication, with column D displaying thepercentage of the preservative in the solution. Column E is themanufacturer of the medication and column F is its classification asover-the counter (OTC) or by prescription (Rx). Columns G, H and Irepresent values from individual trials. The average in Column J iscalculated using the values of G, H and I. Every bottle has a uniquevolume to contain a set amount of medication, which is noted in columnK. The value in column K is divided by the average in column J todetermine the number of doses possible as noted in Column L.

TABLE A Preserv med in in Bottle solution solution RX/ Size Name (%)Preservative (%) Company OTC Trial 1 Trial 2 Trial 3 Avg (ml) DosesBlink tears Sodium Chlorate Advanced OTC 0.041 0.046 0.041 0.0427 15 352Medical Optics thera tears (sodium 0.025 Sodium Perborate Advanced OTC0.046 0.05 0.049 0.0483 30 621 carboxymethylcellulose) Vision ResearchNaphcon A 0.3 Benzalkonium 0.01 Alcon OTC 0.038 0.04 0.04 0.0393 15 381(Pheniramine Chloride Maleate) Opti-free express Polyquad Alcon OTC0.036 0.038 0.038 0.037333 20 535.7 rewetting drops Opti-free ReplenishPolyquad 0.001 Alcon OTC 0.026 0.027 0.029 0.0273 10 366 Systane Balance0.6 Polyquad 0.001 Alcon OTC 0.039 0.035 0.035 0.0363 10 275 (propyleneglycol) Systane Lubricant Polyquad Alcon OTC 0.038 0.044 0.05 0.0440 15341 Eye drops Systane ultra Polyquad 0.001 Alcon OTC 0.047 0.047 0.0490.0477 10 210 Tears Naturale II Polyquad 0.001 Alcon OTC 0.057 0.0560.06 0.0577 15 260 Refresh optive 0.5 PURITE Allergan OTC 0.04 0.0410.04 0.0403 15 372 (Carboxymethylcellulose Sodium) Refresh Tears 0.5PURITE Allergan OTC 0.054 0.055 0.059 0.0560 15 268(Carboxymethylcellulose Sodium) Adv. Eye Relief Dry Benzalkonium 0.01Bausch & OTC 0.027 0.028 0.03 0.0283 15 529 Eye Chloride Lomb Adv. Eyerelief 0.03 Benzalkonium 0.01 Bausch & OTC 0.032 0.031 0.032 0.0317 15474 Redness Chloride Lomb (Naphazoline HCl) Alaway (ketotifen 0.035Benzalkonium 0.01 Bausch & OTC 0.036 0.034 0.035 0.0350 10 286 fumarate)Chloride Lomb Muro128 Bausch & OTC 0.038 0.041 0.038 0.0390 15 385 LombOpcon-A Benzalkonium Bausch & OTC 0.028 0.031 0.032 0.0303 15 495Chloride Lomb Renu Sorbic acid, 0.15 and Bausch & OTC 0.036 0.039 0.0410.0387 15 388 Disodium edetate .1 Lomb Sensitive eyes Sorbic Acid and .1and Bausch & OTC 0.039 0.038 0.04 0.0390 30 769 Disodium edetate .025Lomb Soothe xp polyhexa- Bausch & OTC 0.033 0.033 0.033 0.0330 15 455methylene Lomb biguanide Visine A.C. 0.05 Benzalkonium Johnson & OTC0.036 0.036 0.038 0.0367 15 409 (Tetrahydrozoline Chloride Johnson HCl)Visine Advanced 0.05 Benzalkonium Johnson & OTC 0.038 0.043 0.041 0.040719 467 Relief Chloride Johnson (Tetrahydrozoline HCl) Visine Dry eyerelief Benzalkonium 0.01 Johnson & OTC 0.031 0.03 0.027 0.0293 15 511Chloride Johnson Visine L.R. Long 0.025 Benzalkonium Johnson & OTC 0.0360.036 0.032 0.0347 15 433 Lasting Redness Chloride Johnson Relief(Oxymetazoline HCl) Visine Max Redness 0.05 Benzalkonium Johnson & OTC0.04 0.042 0.042 0.0413 15 363 Relief Chloride Johnson (TetrahydrozolineHCl) Visine original 0.05 Benzalkonium Johnson & OTC 0.034 0.034 0.0340.0340 19 559 (Tetrahydrozoline Chloride Johnson HCl) Visine-A 0.3Benzalkonium 0.01 Johnson & OTC 0.031 0.031 0.033 0.0317 15 474(Pheniramine Chloride Johnson Maleate) Optimum WRW Benzyl Alcohol, .1,.05, Lobob OTC 0.055 0.052 0.058 0.055 30 545.5 (fluorosilicone SorbicAcid, .1 acrylate) Disodium edetate Clear eyes natural BenzalkoniumMedTech OTC 0.026 0.03 0.024 0.0267 15 563 tears lubricant ChlorideProducts Clear eyes Redness 0.012 Benzalkonium MedTech OTC 0.024 0.020.021 0.0217 30 1385 relief (naphazoline Chloride Products HCl) GenTealGenAqua Novartis OTC 0.046 0.046 0.047 0.0463 15 324 (hydroxypropyl(Sodium methylcellulose) perborate) Hypo tears Benzalkonium 0.01Novartis OTC 0.032 0.039 0.038 0.0363 30 826 Chloride Zaditor (ketotifen0.025 Benzalkonium 0.01 Novartis OTC 0.033 0.032 0.034 0.0330 5 152fumarate) Chloride Rohto arctic 0.05 Rohto OTC 0.035 0.03 0.034 0.033013 394 (Tetrahydrozoline HCl) Rohto Cool 0.012 Benzalkonium Rohto OTC0.037 0.033 0.03 0.0333 13 390 (naphazoline HCl) Chloride Rohto Hydra0.3 Rohto OTC 0.041 0.034 0.03 0.0350 13 371 (hypromellose) Rohto ice(Zinc 0.25 Rohto OTC 0.035 0.03 0.038 0.0343 13 379 Sulfate) Similasanallergy eye Silver sulphate Similasan OTC 0.044 0.044 0.046 0.0447 10224 relief Similasan pink eye Silver sulphate Similasan OTC 0.048 0.0450.048 0.0470 10 213 relief Walgreens artificial Benzalkonium 0.01Walgreens OTC 0.028 0.03 0.032 0.0300 30 1000 tears Chloride Walgreenssterile None 0 Walgreens OTC 0.031 0.033 0.036 0.0333 32 artificialtears (ampules) AK-Dilate 2.5 Benzalkonium 0.01 Akorn Rx 0.023 0.0290.029 0.0270 15 556 Phenylephrine Chloride Hydrochloride Azopt(brinzolamide) 1 Benzalkonium 0.01 Alcon Rx 0.039 0.039 0.039 0.0390 10256 Chloride Nevanac (nepafenac) 0.1 Benzalkonium 0.005 Alcon Rx 0.040.039 0.043 0.0407 3 74 Chloride Pataday (olopatadine 0.2 Benzalkonium0.01 Alcon Rx 0.028 0.029 0.027 0.0280 2.5 89 hydrochloride) ChlorideTravatan 0.004 Sofzia Alcon Rx 0.03 0.034 0.034 0.0327 5 153Z(travoprost) vigamox 0.5 None 0 Alcon Rx 0.039 0.045 0.046 0.0433 3 69(moxifloxacin hydrochloride) Ketorolac 0.4 Benzalkonium 0.006Alcon-Falcon Rx 0.025 0.026 0.024 0.0250 5 200 Tromethamine ChloridePrednisolone Acetate 1 Benzalkonium 0.01 Alcon-Falcon Rx 0.03 0.0330.037 0.0333 5 150 Ophthalmic Chloride suspension Proparacaine 0.5Benzalkonium 0.01 Alcon-Falcon Rx 0.036 0.04 0.042 0.0393 15 381Hydrochloride Chloride Ophthalmic solution Tobramycin and 0.4Benzalkonium 0.01 Alcon-Falcon Rx 0.032 0.033 0.029 0.0313 5 160Dexamethasone Chloride Tropicamide 1 Benzalkonium 0.01 Alcon-Falcon Rx0.033 0.028 0.034 0.0317 15 474 Chloride Alphagan P 0.1 PURITE 0.005Allergan Rx 0.041 0.042 0.05 0.0443 5 113 (brimonidine tartrate) Lumigan0.03 Benzalkonium 0.005 Allergan Rx 0.025 0.021 0.022 0.0227 5 221(bimatoprost) Chloride Restasis 0.05 None (Sterile) 0 Allergan Rx 0.0250.023 0.025 0.0243 30 (cyclosporine) (ampules) Zymar (gatifloxacin) 0.3Benzalkonium 0.005 Allergan Rx 0.029 0.031 0.031 0.0303 5 165 ChlorideZymaxid 0.5 Benzalkonium 0.005 Allergan Rx 0.033 0.035 0.032 0.0333 2.575 (gatifloxacin) Chloride Alrex (loteprednol 0.2 Benzalkonium 0.01Bausch & Rx 0.032 0.034 0.033 0.0330 5 152 etabonate) Chloride LombBepreve (bepotastine 1.5 Benzalkonium 0.005 Bausch & Rx 0.031 0.033 0.030.0313 5 160 besilate) Chloride Lomb Besivance 0.6 Benzalkonium 0.01Bausch & Rx 0.036 0.041 0.04 0.0390 5 128 (besifloxacin) Chloride LombLotemax (loteprednol 0.5 Benzalkonium 0.01 Bausch & Rx 0.029 0.031 0.0310.0303 5 165 etabonate) Chloride Lomb Dorzolamide HCl Benzalkonium0.0075 Hi-tech Rx 0.051 0.048 0.053 0.0507 10 197 Timolol MaleateChloride AzaSite 1 Benzalkonium 0.003 Inspire Rx 0.046 0.045 0.0510.0473 2.5 53 (azithromycin) Chloride Bromday 0.09 Benzalkonium Ista Rx0.046 0.04 0.038 0.0413 1.7 41 (bromfenac) Chloride Levofloxacin 0.5Benzalkonium 0.005 Pack Rx 0.028 0.027 0.025 0.0267 5 188 ChlorideXalatan (latanoprost) 0.005 Benzalkonium 0.02 Pfizer Rx 0.022 0.0230.026 0.0237 2.5 106 Chloride Istalol 0.5 Benzalkonium 0.005 Senju Rx0.026 0.031 0.031 0.0293 5 170 Chloride Durezol 0.05 Sorbic Acid 0.1Sirion Rx 0.04 0.039 0.034 0.0377 5 133 (difluprednate) TherapeuticsDorzolamide HCl 2 Benzalkonium 0.0075 Teva Rx 0.036 0.04 0.04 0.0387 10259 Chloride BAK free 0.035 0.033 0.034 0.0340 Latanoprost

What is claimed:
 1. A method of delivering a medicament to an eye of asubject in need thereof a solution, the method comprising: (a) providingdroplets containing said medicament, wherein said droplets have anaverage droplet size of at least about 15 microns and an average initialejecting velocity between 1 m/s and 5 m/s; and (b) delivering saidmedicament to said eye, wherein between about 80% to about 100% of theejected mass of said droplets are deposited on the eye.
 2. The methodaccording to claim 1, wherein said medicament is delivered in an aqueousdroplet solution.
 3. The method according to claim 2, wherein saidmedicament is delivered in an oil/water emulsion droplet.
 4. The methodaccording to claim 3, wherein said oil in said oil/water emulsiondroplet is a glycerin, a castor oil, or a polysorbate 80 mixture.
 5. Themethod according to claim 1, wherein said medicament is a glaucomamedicament.
 6. The method according to claim 1, wherein said medicamentis an antibiotic.
 7. The method according to claim 1, wherein saidaverage droplets ejecting size is in the range of about 30 microns toabout 60 microns.
 8. The method according to claim 1, wherein saidaverage initial droplet ejecting velocity is between about 1 m/s toabout 4 m/s.
 9. The method according to claim 1, wherein said medicamentis selected from the group consisting of ranibizumab antibody FAB(including Lucentis), VEGF Trap fusion molecule (including VEGFTrap-Eye), microplasmin enzyme (including Ocriplasmin), macugenpegylated polypeptide (including Pegaptanib), and bevacizumab (includingAvastin).
 10. The method according to claim 1, wherein said medicamentcomprises a medicament selected from the group consisting ofcarboxymethylcellulose sodium, tetrahydrozoline HCl, pheniraminemaleate, ketotifen fumarate, oxymetazoline HCl, naphazoline HCl,pheniramine maleate, moxifloxacin hydrochloride, bromfenac, proparacainehydrochloride, difluprednate, gatifloxacin, travoprost, bepotastinebesilate, gatifloxacin, loteprednol etabonate, timolol ophthalmic,olopatadine hydrochloride, phenylephrine hydrochloride, levofloxacin,ketorolac tromethamine, letanoprost, bimatoprost and BAK freelatanoprost.
 11. The method according to claim 1, wherein saidmedicament comprises a medicament selected from the group consisting offluorosilicone acrylate, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, tetrahydrozoline HCl, carboxymethylcellulose sodium,propylene glycol, hypromellose, zinc sulfate, dorzolamide HCl timololmaleate, azithromycin, brimonidine tartrate, nepafenac, brinzolamide,besifloxacin, dorzolamide HCl, prenisone acetate, loteprednol etabonate,tobramycin/dexamethasone, and cyclosporine.
 12. The method according toclaim 1, wherein said medicament is selected from the group consistingof travoprost, timolol ophthalmic, latanoprost, bimatoprost, dorzolamideHCl timolol maleate, brimonidine tartrate, brinzolamide, dorzolamideHCl, and BAK free latanoprost.
 13. A method of delivering a medicamentsolution on the eye to a subject in need thereof by controlling averagedroplet size and deposit parameters of said medicament solutioncomprising: (a) determining desired dosage of said medicament solutionfor said subject in need thereof; and (b) providing said desired dosagein a single application by determining said average droplet size anddeposit parameters of said medicament solution on the eye.
 14. Themethod according to claim 13, wherein said medicament is delivered in anaqueous droplet solution.
 15. The method according to claim 14, whereinsaid medicament is delivered in an oil/water emulsion droplet.
 16. Themethod according to claim 15, wherein said oil in said oil/wateremulsion droplet is a glycerin, a castor oil, or a polysorbate 80mixture.
 17. The method according to claim 13, wherein said medicamentis a glaucoma medicament.
 18. The method according to claim 13, whereinsaid medicament is an antibiotic.
 19. The method according to claim 13,wherein said average droplet ejecting size is in the range of about 30microns to about 60 microns.
 20. The method according to claim 13,wherein said average droplet initial ejecting velocity is between about0.5 m/s to about 20 m/s.
 21. The method according to claim 13, whereinsaid medicament is selected from the group consisting of ranibizumabantibody FAB (including Lucentis), VEGF Trap fusion molecule (includingVEGF Trap-Eye), microplasmin enzyme (including Ocriplasmin), macugenpegylated polypeptide (including Pegaptanib), and bevacizumab (includingAvastin).
 22. The method according to claim 13, wherein said medicamentcomprises a medicament selected from the group consisting ofcarboxymethylcellulose sodium, tetrahydrozoline HCl, pheniraminemaleate, ketotifen fumarate, oxymetazoline HCl, naphazoline HCl,pheniramine maleate, moxifloxacin hydrochloride, bromfenac, proparacainehydrochloride, difluprednate, gatifloxacin, travoprost, bepotastinebesilate, gatifloxacin, loteprednol etabonate, timolol ophthalmic,olopatadine hydrochloride, phenylephrine hydrochloride, levofloxacin,ketorolac tromethamine, letanoprost, bimatoprost and BAK freelatanoprost.
 23. The method according to claim 13, wherein saidmedicament comprises a medicament selected from the group consisting offluorosilicone acrylate, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, tetrahydrozoline HCl, carboxymethylcellulose sodium,propylene glycol, hypromellose, zinc sulfate, dorzolamide HCl timololmaleate, azithromycin, brimonidine tartrate, nepafenac, brinzolamide,besifloxacin, dorzolamide HCl, prenisone acetate, loteprednol etabonate,tobramycin/dexamethasone, and cyclosporine.
 24. The method according toclaim 13, wherein said medicament is selected from the group consistingof travoprost, timolol ophthalmic, latanoprost, bimatoprost, dorzolamideHCl timolol maleate, brimonidine tartrate, brinzolamide, dorzolamideHCl, and BAK free latanoprost.
 25. A method for providing a solution tothe eye comprising: (a) providing droplets containing said medicament,wherein said droplets have an average droplet size of at least about 15microns in diameter and an average initial ejecting velocity of betweenabout 1 m/s and 5 m/s; and (b) delivering said medicament to said eye,wherein between about 80% to about 100% of the ejected mass of saiddroplets are deposited on the eye.
 26. The method of claim 25, whereinsaid solution is an isotonic saline solution.
 27. The method accordingto claim 25, wherein said solution comprises a medicament and saidmedicament is delivered in an aqueous droplet solution.
 28. The methodaccording to claim 25, wherein said solution comprises a medicament andsaid medicament is delivered in an oil/water emulsion droplet.
 29. Themethod according to claim 28, wherein said oil in said oil/wateremulsion droplet is a glycerin, a castor oil, or a polysorbate 80mixture.
 30. The method according to claim 27, wherein said medicamentis a glaucoma medicament.
 31. The method according to claim 27, whereinsaid medicament is an antibiotic.
 32. The method according to claim 25,wherein said average droplet ejecting size is in the range of about 30microns to about 60 microns.
 33. The method according to claim 25,wherein said average droplet initial ejecting velocity is between about1 m/s to about 4 m/s.
 34. The method according to claim 27, saidmedicament is selected from the group consisting of ranibizumab antibodyFAB (including Lucentis), VEGF Trap fusion molecule (including VEGFTrap-Eye), microplasmin enzyme (including Ocriplasmin), macugenpegylated polypeptide (including Pegaptanib), and bevacizumab (includingAvastin).
 35. The method according to claim 27, wherein said medicamentcomprises a medicament selected from the group consisting ofcarboxymethylcellulose sodium, tetrahydrozoline HCl, pheniraminemaleate, ketotifen fumarate, oxymetazoline HCl, naphazoline HCl,pheniramine maleate, moxifloxacin hydrochloride, bromfenac, proparacainehydrochloride, difluprednate, gatifloxacin, travoprost, bepotastinebesilate, gatifloxacin, loteprednol etabonate, timolol ophthalmic,olopatadine hydrochloride, phenylephrine hydrochloride, levofloxacin,ketorolac tromethamine, letanoprost, bimatoprost and BAK freelatanoprost.
 36. The method according to claim 27, wherein saidmedicament comprises a medicament selected from the group consisting offluorosilicone acrylate, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, tetrahydrozoline HCl, carboxymethylcellulose sodium,propylene glycol, hypromellose, zinc sulfate, dorzolamide HCl timololmaleate, azithromycin, brimonidine tartrate, nepafenac, brinzolamide,besifloxacin, dorzolamide HCl, prenisone acetate, loteprednol etabonate,tobramycin/dexamethasone, and cyclosporine.
 37. The method according toclaim 27, wherein said medicament is selected from the group consistingof travoprost, timolol ophthalmic, latanoprost, bimatoprost, dorzolamideHCl timolol maleate, brimonidine tartrate, brinzolamide, dorzolamideHCl, and BAK free latanoprost.
 38. A method of treating glaucoma in asubject in need there of comprising: (a) providing droplets containingsaid medicament, wherein said droplets have an average droplet size ofat least about 15 micron in diameter and an average initial ejectingvelocity of between about 1 m/s and 5 m/s; and (b) delivering saidmedicament to said eye, wherein between about 80% to about 100% of theejected mass of said droplets are deposited on the eye.
 39. The methodaccording to claim 38, wherein said medicament is delivered in anaqueous droplet solution.
 40. The method according to claim 39, whereinsaid medicament is delivered in an oil/water emulsion droplet.
 41. Themethod according to claim 40, wherein said oil in said oil/wateremulsion droplet is a glycerin, a castor oil, or a polysorbate 80mixture.
 42. The method according to claim 38, wherein said averagedroplets ejecting size is in the range of about 30 microns to about 60microns.
 43. The method according to claim 38, wherein said averagedroplet initial ejecting velocity is between about 1 m/s to about 4 m/s.44. The method according to claim 38, said medicament is selected fromthe group consisting of travoprost, timolol ophthalmic, latanoprost,bimatoprost, dorzolamide HCl timolol maleate, brimonidine tartrate,brinzolamide, dorzolamide HCl, and BAK free latanoprost.
 45. A method oftreating an infection in a subject in need thereof, comprising: (a)providing droplets containing said medicament, wherein said dropletshave an average droplet size of at least about 15 microns in diameterand an average initial ejecting velocity of between about 1 m/s andabout 5 m/s; and (b) delivering said medicament to said eye, whereinbetween about 80% to about 100% of the ejected mass of said droplets aredeposited on the eye.
 46. The method according to claim 45, wherein saidmedicament is delivered in an aqueous droplet solution.
 47. The methodaccording to claim 45, wherein said medicament is delivered in anoil/water emulsion droplet.
 48. The method according to claim 47,wherein said oil in said oil/water emulsion droplet is a glycerin, acastor oil, or a polysorbate 80 mixture.
 49. The method according toclaim 46, wherein said average droplets ejecting size is in the range ofabout 30 microns to about 60 microns.
 50. The method according to claim46, wherein said average droplet initial ejecting velocity is betweenabout 1 m/s to about 4 m/s.
 51. The method according to claim 46,wherein said medicament comprises a medicament selected from the groupconsisting of tobramycin and gentamycin.
 52. A method of providing areduced dosage form of a medicament to an eye comprising: (a) providingdroplets containing said medicament, wherein said droplets have anaverage droplet size of at least about 15 microns in diameter and anaverage initial ejecting velocity of between 1 m/s and 5 m/s; and (b)delivering said medicament to said eye, wherein between about 80% toabout 100% of the ejected mass of said droplets are deposited on theeye, and wherein said droplets provide a total volume of less than 30 μlto said eye.